Thyroid cancer is the most common endocrine malignancy and ranks as the sixth most common cancer diagnosed in women. Rising incidence of thyroid cancer is reflected by the projected 52,000 new cases in 2019. A majority of patients have differentiated thyroid cancer and are managed successfully with a combination of surgery and radioiodine (RAI) therapy. However, tumors may present or recur as RAI-refractory or metastatic, in which case they have a poorer prognosis and death is common. Among these, anaplastic thyroid cancer (ATC), although relatively rare, represents a true clinical emergency: ATC is typically unresectable at presentation, highly resistant to therapy, RAI-resistant, and associated with a median survival of less than 9 months when patients are treated with multimodal therapy, and less than 3 months with palliative care. Cytotoxic chemotherapy and radiation are generally ineffective in prolonging survival of ATC patients. Thus, ATC remains one of the most lethal tumors and needs novel, effective, and especially rational therapeutic approaches. The major obstacle to this goal is the lack of a detailed understanding of the pathways altered both in the early stages (drivers) and during progression of ATC. As the patient population is small, our mechanistic knowledge is based on the retrospective analysis of patient material and on cell lines often of dubious origin. We now know that TP53 is lost or mutated in 70% of ATCs, and that in almost 40% the PI3K cascade is constitutively activated. Additional common drivers include BRAF (40%) and RAS (27%) activating mutations. Despite this knowledge, it is increasingly clear that we are still missing a comprehensive wiring chart depicting all the interactions between different, cooperating driver pathways. Such detailed map is of paramount importance to design effective multidrug combinations that consider less known signaling conduits, mechanisms of resistance, and feedback pathway activation. The current application has two broad, long-term objectives. The first goal is to utilize a combination of in vivo, ex vivo, and in vitro approaches to test the hypothesis that activation and/or overexpression of the SGK1 protein kinase are integral and essential components of the neoplastic transformation process initiated by constitutive activation of PI3K, RAS, and SRC in thyroid epithelial cells and that SGK1 targeting is essential for effective inhibition of tumor growth. The second objective is to use genetically engineered mouse models, as well as cell culture approaches, to test the hypothesis that mutations in mTORC1-activating pathways, including loss of NF2 and activation of PI3K signaling, cooperate with oncogenic RAS by contributing crucial signals needed for RAS-mediated transformation of thyroid epithelial cells. This genetic interaction opens a window of opportunity for targeted therapeutic approaches.